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J. Biol. Chem., Vol. 279, Issue 17, 17772-17784, April 23, 2004

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PE-1/METS, an Antiproliferative Ets Repressor Factor, Is Induced by CREB-1/CREM-1 during Macrophage Differentiation^*

Dominique Sawka-Verhelle, Laure Escoubet-Lozach, Amy L. Fong, Kelly D. Hester, Stephan Herzig, Patricia Lebrun, and Christopher K. Glass¶||

From the Departments of Cellular and Molecular Medicine and ^¶Medicine, University of California at San Diego, La Jolla, California 92093 and the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037-1002

The molecular mechanisms involved in regulating the balance between cellular proliferation and differentiation remain poorly understood. Members of the Ets-domain family of transcription factors are candidates for proteins that might differentially regulate cell cycle control and cell type-specific genes during the differentiation of myeloid progenitor cells. The Ets repressor PE-1/METS has been suggested to contribute to growth arrest during terminal macrophage differentiation by repressing Ets target genes involved in Ras-dependent proliferation. An important feature of this regulatory model is that PE-1/METS is itself induced by the program of macrophage differentiation elicited by M-CSF. Here, we present evidence that the PE-1/METS gene is a transcriptional target of the cyclic AMP response element-binding protein-1 (CREB-1). CREB-1 expression is dramatically up-regulated during macrophage differentiation and phosphorylation of CREB-1 and the related factor CREM-1 are stimulated by M-CSF in a SAPK2/p38-dependent manner. Chromatin immunoprecipitation experiments demonstrate that CREB-1/CREM-1 are recruited to the PE-1/METS promoter as well as to the promoters of other genes that are up-regulated during terminal macrophage differentiation. Overexpression of CREB-1 stimulates the activities of the PE-1/METS, and macrosialin promoters, while expression of a dominant negative form of CREB-1 during macrophage differentiation inhibits expression of the PE-1/METS and macrosialin genes. Inhibition of CREB function also results in reduced expression of CD54 and impaired cell adhesion. Taken together, these findings reveal new roles of CREB-1/CREM-1 as regulators of macrophage differentiation.

Received for publication, October 31, 2003 , and in revised form, January 26, 2004.

The atomic coordinates and structure factors (code AY274927) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* These studies were supported in part by National Institutes of Health Grant HL59694-06, by postdoctoral fellowships (to D. S.-V.; ARC and Leukemia and Lymphoma Society (Grant 5388-02), and L. E.L; ARC), and by NCI, National Institutes of Health Cancer Cell Biology Training Grant T32-CA67754 (to A. L. F). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 858-534-6011; Fax: 858-822-2127; E-mail: cglass{at}ucsd.edu.

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